Skin Manifestations of Chronic Hepatitis C Virus Infection - Dermatology Advisor

Skin Manifestations of Chronic Hepatitis C Virus Infection

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  • Photo Credit: Allan Harris.

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    Photo Credit: Allan Harris.

  • Cryoglobulins are immunoglobulin (Ig) complexes that precipitate from the serum at low blood temperatures (<37°C) and then redissolve during incubation.1 Cryoglobulinemia occurs when excess cryoglobulins circulate in serum, resulting in different clinical manifestations based on the immunologic composition of the cryoglobulins. Three immunochemical types of cryoglobulins have been described. Of these, type 2, or MC, is most commonly found in patients with chronic HCV infection, with HCV infection accounting for 95% of all MC cases.1,2 Patients with MC have a mixture of circulating monoclonal IgMs and polyclonal IgGs, with the IgMs having rheumatoid factor (RF) positivity. Rarely, patients with chronic HCV infection may have immunochemical type 3, in which both IgM and IgG are polyclonal. Patients with type 2 or 3 cryoglobulinemia should be screened for HCV infection, and those with HCV and worsening renal function or cutaneous involvement should be tested for cryoglobulinemia.3 Photo Credit: ISM/Pr JL KEMENY.

    Mixed Cryoglobulinemia (MC) Overview

    Cryoglobulins are immunoglobulin (Ig) complexes that precipitate from the serum at low blood temperatures (<37°C) and then redissolve during incubation.1 Cryoglobulinemia occurs when excess cryoglobulins circulate in serum, resulting in different clinical manifestations based on the immunologic composition of the cryoglobulins. Three immunochemical types of cryoglobulins have been described. Of these, type 2, or MC, is most commonly found in patients with chronic HCV infection, with HCV infection accounting for 95% of all MC cases.1,2

    Patients with MC have a mixture of circulating monoclonal IgMs and polyclonal IgGs, with the IgMs having rheumatoid factor (RF) positivity. Rarely, patients with chronic HCV infection may have immunochemical type 3, in which both IgM and IgG are polyclonal. Patients with type 2 or 3 cryoglobulinemia should be screened for HCV infection, and those with HCV and worsening renal function or cutaneous involvement should be tested for cryoglobulinemia.3

    Photo Credit: ISM/Pr JL KEMENY.

  • Patients with MC HCV most commonly present with palpable purpura, arthralgia, and weakness.1 Purpura usually occurs as petechial lesions in the legs that can extend to the abdomen.3 Rarely, they may reach the upper extremities. Arthralgias typically affect hand joints, wrists, and knees, without signs of inflammation or evidence of bone erosion. Although weakness and fatigue are subjective, patients experience sensory symptoms (eg, paresthesia) before motor weakness. Other manifestations of MC may include livedo reticularis, Raynaud's phenomenon, and digital ischemia and necrosis.3 MC is typically diagnosed on the basis of patient history, clinical manifestations, and laboratory findings. Findings suggestive of MC include the presence of cryoglobulins; RF positivity; false elevation of white blood cells or platelets; detection of hypocomplementemia, particularly low C4; and presence of markers of chronic inflammation, such as elevated erythrocyte sedimentation rate and C-reactive protein.1,3 Photo Credit: Medical Images RM/BOB TAPPER.

    MC Presentation and Diagnosis

    Patients with MC HCV most commonly present with palpable purpura, arthralgia, and weakness.1 Purpura usually occurs as petechial lesions in the legs that can extend to the abdomen.3 Rarely, they may reach the upper extremities. Arthralgias typically affect hand joints, wrists, and knees, without signs of inflammation or evidence of bone erosion. Although weakness and fatigue are subjective, patients experience sensory symptoms (eg, paresthesia) before motor weakness. Other manifestations of MC may include livedo reticularis, Raynaud's phenomenon, and digital ischemia and necrosis.3

    MC is typically diagnosed on the basis of patient history, clinical manifestations, and laboratory findings. Findings suggestive of MC include the presence of cryoglobulins; RF positivity; false elevation of white blood cells or platelets; detection of hypocomplementemia, particularly low C4; and presence of markers of chronic inflammation, such as elevated erythrocyte sedimentation rate and C-reactive protein.1,3

    Photo Credit: Medical Images RM/BOB TAPPER.

  • Lichen planus (LP) is a chronic, inflammatory, papulosquamous, autoimmune disease that is estimated to occur in <1% of the general population.1 It appears to be more common in individuals with HCV, with 1 study reporting a 4.80 times higher prevalence in this population.4 LP can affect the skin, scalp, genitals, oral cavity and other mucus membranes, and nails. Its etiology is not well understood, but genetic, environmental, and lifestyle factors are thought to play a role. An immune mechanism directed by activated CD81 T cells against basal keratinocytes has been suggested to play a major role in the pathophysiology of the disease, with cytokines such as tumor necrosis factor-α, interferon-γ, and interleukin-6 and interleukin-8 thought to contribute in the setting of HCV infection.1 Cutaneous LP is a self-limited disease that usually resolves within 6 to 12 months and mainly affects adults. Photo Credit: ISM/CID.

    Lichen Planus Overview

    Lichen planus (LP) is a chronic, inflammatory, papulosquamous, autoimmune disease that is estimated to occur in <1% of the general population.1 It appears to be more common in individuals with HCV, with 1 study reporting a 4.80 times higher prevalence in this population.4 LP can affect the skin, scalp, genitals, oral cavity and other mucus membranes, and nails. Its etiology is not well understood, but genetic, environmental, and lifestyle factors are thought to play a role. An immune mechanism directed by activated CD81 T cells against basal keratinocytes has been suggested to play a major role in the pathophysiology of the disease, with cytokines such as tumor necrosis factor-α, interferon-γ, and interleukin-6 and interleukin-8 thought to contribute in the setting of HCV infection.1 Cutaneous LP is a self-limited disease that usually resolves within 6 to 12 months and mainly affects adults.

    Photo Credit: ISM/CID.

  • Classic LP typically presents as pruritic, polygonal, violaceous flat-topped papules or plaques on the flexural surfaces of the wrists and forearm and/or extensor surface of the hands, ankles, and shins.1,4,5 Although LP can affect any part of the body, the face is rarely involved.5 LP lesions typically have a symmetric distribution. Papules often appear dry and shiny, with branny scales that form fine, whitish streaks (ie, Wickham's striae).5 Depending on lesion location, patients may report pain, itching, hair loss, scalp discoloration, and nail damage or loss. LP is diagnosed on the basis of history and physical examination, including visual inspection of the entire cutaneous surface and oral cavity. A punch or shave biopsy extending to the middermis can help make a definitive diagnosis. Photo Credit: Hercules Robinson.

    LP Presentation and Diagnosis

    Classic LP typically presents as pruritic, polygonal, violaceous flat-topped papules or plaques on the flexural surfaces of the wrists and forearm and/or extensor surface of the hands, ankles, and shins.1,4,5 Although LP can affect any part of the body, the face is rarely involved.5 LP lesions typically have a symmetric distribution. Papules often appear dry and shiny, with branny scales that form fine, whitish streaks (ie, Wickham's striae).5 Depending on lesion location, patients may report pain, itching, hair loss, scalp discoloration, and nail damage or loss.

    LP is diagnosed on the basis of history and physical examination, including visual inspection of the entire cutaneous surface and oral cavity. A punch or shave biopsy extending to the middermis can help make a definitive diagnosis.

    Photo Credit: Hercules Robinson.

  • Porphyria is a group of disorders that result from abnormalities in enzymatic activity during heme and porphyrin synthesis. Although porphyria cutanea tarda (PCT) is the most common form of these disorders, it is rare, affecting an estimated 1 in 25,000 people in the United States.1 PCT results when there is a deficiency of the enzyme uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the biosynthesis of heme, resulting in excess build-up of porphyrins in the liver and skin.6 PCT can be subdivided into 2 types: sporadic (type 1), making up 80% of cases, and familial (type 2), making up 20% of cases. Those with familial PCT have a mutation in their UROD gene, whereas those with sporadic PCT do not. Regardless of type, PCT usually remains latent until an activating factor is present, such as HCV infection. Worldwide studies have shown the prevalence of sporadic PCT among patients with HCV to range from >70% to about 50%.1 The mechanism through which HCV infection leads to PCT remains unknown.1,6 Photo Credit: ISM/CID.

    Porphyria Cutanea Tarda Overview

    Porphyria is a group of disorders that result from abnormalities in enzymatic activity during heme and porphyrin synthesis. Although porphyria cutanea tarda (PCT) is the most common form of these disorders, it is rare, affecting an estimated 1 in 25,000 people in the United States.1 PCT results when there is a deficiency of the enzyme uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the biosynthesis of heme, resulting in excess build-up of porphyrins in the liver and skin.6

    PCT can be subdivided into 2 types: sporadic (type 1), making up 80% of cases, and familial (type 2), making up 20% of cases. Those with familial PCT have a mutation in their UROD gene, whereas those with sporadic PCT do not. Regardless of type, PCT usually remains latent until an activating factor is present, such as HCV infection. Worldwide studies have shown the prevalence of sporadic PCT among patients with HCV to range from >70% to about 50%.1 The mechanism through which HCV infection leads to PCT remains unknown.1,6

    Photo Credit: ISM/CID.

  • PCT manifests when hepatic UROD activity is <20% of normal.1 As porphyrins accumulate in the liver, they are transported to the skin, leading to phototoxicity as light exposure causes the porphyrins to release photons.1 Subsequently, patients develop blisters on sun-exposed areas of their skin, particularly the hands, face, neck, and forearms. These areas are also prone to blisters and peeling after mild trauma. When the lesions scar, they may resemble systemic scleroderma. In some cases, lesions become painful. Patients may also have abnormal hair growth, skin thickening, and hypopigmentation. PCT is diagnosed when elevated porphyrins are detected in the plasma. Urine and fecal studies can confirm the diagnosis when they show similarly elevated porphyrin levels, with urine typically showing excess uroporphyrin and 7-carboxylate porphyrin and feces showing excess isocoproporphyrin.6 Patients with a PCT diagnosis should be tested for HCV if their status is unknown. Photo Credit: Dr Harout Tanielian/Science Source.

    PCT Presentation and Diagnosis

    PCT manifests when hepatic UROD activity is <20% of normal.1 As porphyrins accumulate in the liver, they are transported to the skin, leading to phototoxicity as light exposure causes the porphyrins to release photons.1 Subsequently, patients develop blisters on sun-exposed areas of their skin, particularly the hands, face, neck, and forearms. These areas are also prone to blisters and peeling after mild trauma. When the lesions scar, they may resemble systemic scleroderma. In some cases, lesions become painful. Patients may also have abnormal hair growth, skin thickening, and hypopigmentation.

    PCT is diagnosed when elevated porphyrins are detected in the plasma. Urine and fecal studies can confirm the diagnosis when they show similarly elevated porphyrin levels, with urine typically showing excess uroporphyrin and 7-carboxylate porphyrin and feces showing excess isocoproporphyrin.6 Patients with a PCT diagnosis should be tested for HCV if their status is unknown.

    Photo Credit: Dr Harout Tanielian/Science Source.

  • Psoriasis is a chronic, immune-mediated skin disorder, affecting ~2% of the US general population.7 Characteristic findings include well-demarcated symmetrical erythematous patches or plaques with silver scales. Psoriasis appears to be more common in people with certain comorbidities, including HCV. In a single-institution study from Japan, where estimated prevalence is <1%, HCV infection was identified in 7.5% of psoriatic patients (54 of 717).8,9 In ~80% of cases, HCV infection preceded onset of psoriasis, but HCV treatment was also found to cause new lesions or exacerbate existing ones.8 A recently published small study assessed the relationship between HCV and psoriasis by comparing biopsies of patients with psoriatic with (n=7) and without (n=10) HCV.10 The findings suggest HCV increases susceptibility to psoriasis by upregulating inflammatory cytokines, including cathelicidin, TLR9, and interferon γ.10 The association between HCV, HCV treatment, and psoriasis requires elucidation in larger, prospective studies. Photo Credit: Hercules Robinson.

    Psoriasis

    Psoriasis is a chronic, immune-mediated skin disorder, affecting ~2% of the US general population.7 Characteristic findings include well-demarcated symmetrical erythematous patches or plaques with silver scales. Psoriasis appears to be more common in people with certain comorbidities, including HCV. In a single-institution study from Japan, where estimated prevalence is <1%, HCV infection was identified in 7.5% of psoriatic patients (54 of 717).8,9 In ~80% of cases, HCV infection preceded onset of psoriasis, but HCV treatment was also found to cause new lesions or exacerbate existing ones.8

    A recently published small study assessed the relationship between HCV and psoriasis by comparing biopsies of patients with psoriatic with (n=7) and without (n=10) HCV.10 The findings suggest HCV increases susceptibility to psoriasis by upregulating inflammatory cytokines, including cathelicidin, TLR9, and interferon γ.10 The association between HCV, HCV treatment, and psoriasis requires elucidation in larger, prospective studies.

    Photo Credit: Hercules Robinson.

  • Necrolytic acral erythema (NAE) is a rare dermatologic disorder associated with HCV and zinc deficiency.1,11 In a small Egyptian study, all 30 patients with NAE were found to have HCV.12 In a case report, a patient with HCV had her NAE resolve after she started taking oral zinc, despite not treating her HCV.11 HCV has been postulated to alter the regulation of zinc, leading to zinc deficiency and subsequent NAE.11 Therefore, all patients with NAE should be tested for HCV and have their zinc levels assessed. Initially, NAE presents as erythematous or violaceous papules, bullae, and erosions, predominately affecting the dorsal surface of the feet and toes, but other parts of the legs and body can be affected.11 As NAE progresses, well-demarcated plaques with erythema on their outer rim, lichenification, secondary hyperpigmentation, and fine desquamation on the skin surface begin to appear.11 Patients may report pruritus, pain, burning, and dysesthesia. Clinical and histology findings can help make the diagnosis. Photo Credit: Dr P Marazzi/Science Source.

    Necrolytic Acral Erythema

    Necrolytic acral erythema (NAE) is a rare dermatologic disorder associated with HCV and zinc deficiency.1,11 In a small Egyptian study, all 30 patients with NAE were found to have HCV.12 In a case report, a patient with HCV had her NAE resolve after she started taking oral zinc, despite not treating her HCV.11 HCV has been postulated to alter the regulation of zinc, leading to zinc deficiency and subsequent NAE.11 Therefore, all patients with NAE should be tested for HCV and have their zinc levels assessed.

    Initially, NAE presents as erythematous or violaceous papules, bullae, and erosions, predominately affecting the dorsal surface of the feet and toes, but other parts of the legs and body can be affected.11 As NAE progresses, well-demarcated plaques with erythema on their outer rim, lichenification, secondary hyperpigmentation, and fine desquamation on the skin surface begin to appear.11 Patients may report pruritus, pain, burning, and dysesthesia. Clinical and histology findings can help make the diagnosis.

    Photo Credit: Dr P Marazzi/Science Source.

  • Pruritus is a common dermatological symptom in the chronic HCV setting, reported to affect approximately 15% to 20% of patients.1,13 Pruritus can occur as a part of another skin disorder associated with HCV or be a direct result of HCV's effects on the liver. It can also be associated with HCV treatment, including direct-acting antivirals, although it is less common with these treatments vs older regimens, such as interferon and ribavirin.1 Patients may present with generalized or localized pruritus on normal-appearing skin or have other skin findings, such as excoriations and lichenification, particularly if another skin condition is present. Some patients have even reported feeling like their internal organs are itching.13 Pruritus should be evaluated in all patients with HCV, as it can have a significant effect on quality of life and might indicate worsening liver disease, as the condition is most prevalent in those with advanced liver disease and cirrhosis.13 Photo Credit: Hercules Robinson.

    Pruritus

    Pruritus is a common dermatological symptom in the chronic HCV setting, reported to affect approximately 15% to 20% of patients.1,13 Pruritus can occur as a part of another skin disorder associated with HCV or be a direct result of HCV's effects on the liver. It can also be associated with HCV treatment, including direct-acting antivirals, although it is less common with these treatments vs older regimens, such as interferon and ribavirin.1

    Patients may present with generalized or localized pruritus on normal-appearing skin or have other skin findings, such as excoriations and lichenification, particularly if another skin condition is present. Some patients have even reported feeling like their internal organs are itching.13 Pruritus should be evaluated in all patients with HCV, as it can have a significant effect on quality of life and might indicate worsening liver disease, as the condition is most prevalent in those with advanced liver disease and cirrhosis.13

    Photo Credit: Hercules Robinson.

Acute and chronic hepatitis C virus (HCV) infection can affect the liver as well as nonhepatic tissues, including the skin. Mixed cryoglobulinemia, porphyria cutanea tarda, lichen planus, and necrolytic acral erythema are the cutaneous diseases most commonly associated with HCV infection, but other skin conditions and symptoms have been associated with HCV, such as psoriasis or pruritus. In some cases, cutaneous manifestations may be the first indication of HCV and should prompt HCV testing. In most cases, skin manifestations disappear after appropriate HCV treatment or viral clearance.

Compiled by Christina Loguidice

References

  1. Sayiner M, Golabi P, Farhat F, Younossi ZM. Dermatologic manifestations of chronic hepatitis C infection.  Clin Liver Dis. 2017;21:555-564.
  2. Misiani R, Bellavita P, Fenili D, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med. 1992;117:573-577.
  3. Dharel N. Cryoglobulinemia (hepatitis C). Accessed January 17, 2018.
  4. Lodi G, Giuliani M, Majorana A, et al. Lichen planus and hepatitis C virus: a multicenter study of patients with oral lesions and a systematic review. Br J Dermatol. 2004;151:1172-1181.
  5. Weston G, Payette M. Update on lichen planus and its clinical variants.  Int J Womens Dermatol. 2015;1:140-149.
  6. American Porphyria Foundation. Porphyria Cutanea Tarda (PCT). Accessed January 22, 2018.
  7. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. 2005;64(Suppl 2):ii18-ii85.
  8. Imafuku S, Nakayama J. Profile of patients with psoriasis associated with hepatitis C virus infection. J Dermatol. 2013;40:428-433.
  9. World Health Organization. Global report on psoriasis. Published 2016. Accessed January 22, 2018.
  10. Chun K, Afshar M, Audish D, et al. Hepatitis C may enhance key amplifiers of psoriasis. J Eur Acad Dermatol Venereol. 2017;31:672-678.
  11. Botelho LFF, Enokihara MMS e S, Enokihara MY. Necrolytic acral erythema: a rare skin disease associated with hepatitis C virus infection. An Bras Dermatol. 2016;91:649-651.
  12. Abdallah MA, Ghozzi MY, Monib HA, et al. Necrolytic acral erythema: a cutaneous sign of hepatitis C virus infection. J Am Acad Dermatol. 2005;53:247-251.
  13. Mazoff CD. Pruritus (Itching). Published November 2014. Accessed January 23, 2018.
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